Drug formulations for coating medical devices

ABSTRACT

The present invention relates to oil-based formulations of hydrophobic drugs for the uniform coating of medical devices such as vascular stents and balloons. Another aspect of the present invention is an intravascular medical device having an oil-based coating suitable for delivering a water-insoluble drug, comprising one or more of an anti-oxidant, an anti-inflammatory and an anti-restenotic agent.

RELATED APPLICATIONS

[0001] This Applications claims the benefit of U.S. Provisional PatentApplication No. 60/446,318 filed Feb. 7, 2003.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention is related to the delivery of drugs fromimplantable medical devices. More specifically, the present inventionrelates to formulations of hydrophobic anti-oxidant, anti-inflammatoryand anti-restenotic agents and vascular stents and balloons having anoil-based coating suitable for delivering anti-oxidant,anti-inflammatory and anti-restenotic agents.

[0004] 2. Description of the Related Art

[0005] Over one million angioplasty procedures are performed annuallywith about 80% of these involving the placement of a metal stent.Although, both balloon angioplasty and stenting of clogged coronaryarteries result in an immediate clearing of the obstruction andresumption of coronary blood flow, within six months 20-50% of thearteries require revascularization. The mechanism of restenosis has beenfound to be related to both mechanical stretch injury and remodeling ofthe artery wall due to smooth muscle cell proliferation into the lumencalled neointimal hyperplasia (NIH). In both instances, the cause of thereduced artery flow is actually induced by balloon angioplasty and/orplacement of the stent. Originally, balloon angioplasty by itself wasresponsible for stretch injury and recoil that lead to as much as 50%restenosis in susceptible patients. To counter the effects of recoil andprop the artery open further, the practice of deploying a metal stentwas introduced and the values of restenosis have dropped to between20-30% depending on the patient population.

[0006] Drugs such as rapamycin and paclitaxel have been demonstrated toreduce NIH and further reduce the rate of stenosis when coated on ametal stent. These drugs act to prevent smooth muscle cell (SMC)proliferation which is a direct consequence of the damage done to theinternal elastica and the medial layers during the deployment of theballoon and/or stent. A new agent C6-ceramide (CERACOR™)—a waterinsoluble lipid, has also been demonstrated to inhibit SMC proliferationin both in vitro cell culture and in vivo animal studies (rabbit carotidmodel and pig coronary) (Charles et al. 2000 Circ Res 87:282-288).C6-ceramide has been shown to initiate activity within 15 minutes ofapplication of a single dose from an angioplasty balloon.

[0007] Initial experiments with C6-ceramide coated on the balloon from adimethylsulfoxide/ethanol solution revealed that the physical form ofthe drug changes with time. Initially, the deposited lipid form atranslucent film, but within an hour or so the deposited material slowlytransforms to a white crystallite appearance. The deposition uniformityas measured by microscopy is spotty across the balloon surface. Afterseveral days, the white powder continues to transform until it flakesoff the balloon and is no longer believed to be in an available state.Decreased availability may be described as the dissolution/deaggregationtime of the solid relative to deposition and diffusion within theartery, which prevents it from exerting its effect. Currently, to studythe effect of C6-ceramide in animal models, the DMSO/ethanol formulationcontaining C6-ceramide is coated onto the balloon just prior toinsertion into the artery. The role of the solvent is to keep the lipidmaterial in an available film-like state sufficient for it to be rapidlydeposited and absorbed quickly in the artery, where it is shown to exertan effect within 15 minutes. However, organic solvents, in which thedrug is very soluble, tend to evaporate rapidly and the solvents mayalso penetrate and affect the balloon performance. Alternative solventsand formulations are needed that permit the drug to remain in adissolved state yet remain physically stable without changing with time.

SUMMARY OF THE INVENTION

[0008] In one embodiment, the present invention relates to a formulationfor coating a medical device with a hydrophobic restenosis-inhibitingagent. The formulation comprises the hydrophobic restenosis-inhibitingagent, a non-volatile oil-based solvent, and an amount of a volatilesolvent sufficient to decrease the viscosity of the non-volatileoil-based solvent, such that the formulation is adapted to uniformlycoat the medical device.

[0009] In a preferred embodiment of the coating formulation, thehydrophobic restenosis-inhibiting agent is C6-ceramide. In anotherpreferred variation of the coating formulation, the non-volatileoil-based solvent comprises Vitamin E. Preferably, the volatile solventcomprises ethanol. In one particularly preferred embodiment, thepharmaceutical formulation, comprising C6-ceramide and Vitamin E.

[0010] In another aspect, the present invention relates to animplantable medical device comprising a surface adapted to contact avessel wall, wherein the surface has a coating comprising a hydrophobicrestenosis-inhibiting agent, and a non-volatile oil-based solvent inwhich said agent is dissolved. This device may be an intravascularballoon. In a variation, the device may be an intravascular stent.Preferably, the oil-based solvent comprises Vitamin E. More preferably,the device is coated with Vitamin E and C6-ceramide.

[0011] In another aspect, the present invention relates to a method forproducing a drug-coated intravascular device. The method comprises thesteps of producing a coating composition by mixing a drug compositioncomprising a water-insoluble restenosis inhibiting agent and anoil-based non-volatile solvent in a volatile solvent; coating theintravascular device with the coating composition; and causing thevolatile solvent to evaporate. Preferably, the oil-based non-volatilesolvent comprises Vitamin E, and the volatile solvent comprises ethanol.Preferably, the restenosis-inhibiting agent is C6-ceramide. In a furtheraspect, the present invention is the drug-coated intravascular deviceproduced by the above method.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012]FIG. 1 shows the results of screening of activity of severalformulations in the rabbit carotid stretch injury model.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0013] In one embodiment, the present invention is an oil-basedformulation of hydrophobic anti-restenosis drugs for uniform coating ofa medical implantable device such as a vascular balloon or a stent.

[0014] In another embodiment, the present invention is a method ofcoating of medical implantable devices such as vascular balloons andstents with water-insoluble drugs dissolved in an oil-based solvent.

[0015] In another embodiment, the present invention is a medicalimplantable device such as a vascular balloon or a stent coated with anoil-based formulation containing a water-insoluble drug.

[0016] For the purpose of this invention by a water-insoluble drug, orhydrophobic drug we mean a drug with a water solubility of less thanabout 1 mg/ml at room temperature and a logP, where P is the partitioncoefficient between octanol and water, of at least 1.5, preferably atleast 2.

[0017] Three formulation approaches have shown significant promise forthe delivery of rapidly acting water-insoluble drugs to the coronaryarteries.

[0018] Formulation Approach 1: Propylene glycol+Surfactant.

[0019] Formulation Approach 2: Intravenously acceptable oils(cottonseed, peanut), Vitamin E.

[0020] Formulation approach 3: Propylene glycol+Surfactant+oil.

[0021] C6-ceramide was found to be sufficiently soluble and/dispersiblein all three formulation approaches when all components were firstdissolved in a volatile solvent, such as ethanol. In all cases the drugwas coated onto a balloon from an ethanol solution containingC6-ceramide and the other solvents in each formulation. Once the ethanolevaporated from the surface of the device, the drug was uniformlydispersed over the surface and dissolved within the non-volatilesolvent(s). The ethanol was useful in that it decreased the viscosity ofthe oil/drug mixture thereby promoting uniform coating. It was foundthat although the oils, other than vitamin E, formed an emulsion withethanol, the coating performance was adequate.

[0022] In all cases the C6-ceramide coated onto the angioplasty balloonin a formulation containing a non-volatile solvent appeared to maintainthe drug in the dissolved state rather than forming a dispersed solid,as was the case for DMSO formulations. Maintaining the drug in thedissolved state uniformly coated over the surface of the balloon isdesirable for improving uniformity of delivery to the artery wall.

[0023] Additional water-insoluble drugs may be used depending on theirsolubility and coating performance, including rapamycin, rapamycinanalogs, ABT-578, everolimus, paclitaxel, dexamethasone and other lipidmaterials (e.g., other ceramides, dimethyl sphingosine, ether-linkeddiglycerides, ether-linked phosphatidic acids, and sphinganines, andother phospholipids). Indeed other compounds could be dispersed in theoil-based formulation of the present invention. Particularly in caseswhere, even if they had low solubility in the oil itself, sufficientdrug could be dispersed either by using appropriate cosolvents andsurfactants or by making a dispersed paste of the hydrophobic drug inthe oil.

[0024] The following exemplary hydrophobic materials that may also becompatible with this oil dispersion approach include but are not limitedto: steroids such as Dexamethasone, 17-beta-Estradiol; Rapamycin andanalogues; Taxol (paclitaxel) and analogues; Actinomycin D;Prostaglandins (PGE1); Vitamin A; Probucol; Batimastat; Statins (HMG-CoAReductase Inhibitors), particularly the water insoluble base forms thatcan be formulated as dispersions in the oil; Trapidil (and otheranti-proliferative Growth Factor Inhibitors); and Cytochalasin B.

[0025] The devices which may be enhanced by coating with theformulations of the present invention include any intraluminal devicesadapted for delivery to selected sites within the cardiovascular system.These include, for example, simple catheter/simple (one) balloondesigns, dual balloon catheters, stents, microporous catheters infusioncatheters, rotary atherectomy devices, ablation catheters, polymeric(e.g., polyacrylic acid) coated balloon designs, bioabsorbable coatingdesigns, stent covers and perivascular matrices.

[0026] The device to be coated is preferably dipped in a vehicleincluding a volatile solvent (e.g., ethanol), a non-volatile oil-basedsolvent, and a hydrophobic drug. The actual coating process may beperformed in a clean environment. If the device has a balloon, it ispreferably expanded prior to coating. Once the volatile solventevaporates from the surface of the device, the drug is uniformlydispersed over the surface of the device and dissolved or dispersedwithin the non-volatile solvent or carrier. Post-processingsterilization can be accomplished by any methods known in the art whichdo not negatively impact the drug activity, the quality of the coatingand/or device itself. For example, the coated device can be subjected toradiation sterilization.

[0027] When coated onto a standard commercially available angioplastyballoon/delivery system, the oil-based formulations containing a waterinsoluble drug:

[0028] uniformly coat the surface of the expanded balloon;

[0029] the coated balloon can be deflated and re-wrapped to permittransport to the coronary artery lesion site with the smallest crossingprofile;

[0030] when redeployed the oil-based C6-ceramide coating remainsdispersed over the entire surface of the balloon;

[0031] little dissolution or removal of the drug from the surface occursprior to inflation of the balloon in the artery;

[0032] the basis of drug transport remains transfer of drug from thesurface of the balloon to the artery wall during inflation of theballoon. The amount of drug transferred is typically less than 25% ofthe total amount of drug available on the surface;

[0033] after inflation the balloon can be rewrapped and removed from theartery or redeployed elsewhere to another lesion site, little drug islost during removal process; and

[0034] the oil-based formulations provide for a lubricious coating tothe balloon without using polymers or hydrogels.

[0035] When used to coat metal coronary stents the oil-basedformulations permit:

[0036] uniform coating of the entire metal surface;

[0037] coating can be applied to both the stent and the delivery balloonat the same time;

[0038] unlike the balloon-coated option that is removed from the arteryimmediately after deployment, the coated stent remains in place and willslowly deliver the entire amount of drug to the artery wall. Thedissolution rate of the oil-based hydrophobic drug system is compatiblewith sustained release delivery of the drug to the artery wall without acontrolling polymer or hydrogel; and

[0039] wound healing potential as vitamin E's antioxidant activity mayaugment the anti-restenotic activity of the drug and enhance woundhealing at the site where the stent struts are embedded in the arterywall.

[0040] The current formulation approach applied to an angioplastyballoon demonstrates rapid pressure transfer delivery of a sufficientamount of water-insoluble materials to the artery wall using anon-polymer/hydrogel base consisting of oil capable of dispersing thedrug. The formulation approach works to keep a lipid material in a verydeliverable form without further solid-state changes that could lead toineffective delivery. The delivery of the drug is largely based oncontact of the balloon surface to the artery wall and the coatinguniformity of the oil-based formulations is superior to other organicsolvents. By increasing the coating uniformity the resultant depositionof the drug on the artery wall will be uniform as well as possiblyimproving the overall activity of the drug.

[0041] The formulation approach outlined here is applicable to bothstents and balloons. For a stent, the viscosity and dissolution rate ofthe resulting oil/drug mixture is tunable based on the concentration ofboth oil and drug. Enhanced wound healing and anti-oxidant behaviorlikely will increase when the choice of the oil is vitamin E possiblyleading to a synergistic effect of the drug/oil mixture. Other possibleoils that can be used in the present invention include but are notlimited to: fish oils (for example, EPA, eicosapentanenoic acid, andDHA, docosahexaenoic acid); vegetable oils (for example, cottonseed,corn, sassafras, sunflower oils), and Vitamin A. Various surfactantsknown in the art may be used in the present invention, for example,Polyoxyl 40 Stearate (Myrj 52), lecithin, Poloxamer, and the like.

[0042] The compatibility of the oil-based formulation approach to thedelivery of many different classes of compounds permits the combinationof anti-oxidant, anti-inflammatory and anti-restenotic agents into onedelivery vehicle that could be an important weapon in the prevention ofrestenosis.

[0043] This invention is further illustrated by the following exampleswhich should not be construed as limiting. It should be appreciated bythose of skill in the art that the techniques disclosed in the exampleswhich follow represent techniques discovered by the inventor to functionwell in the practice of the invention, and thus can be considered toconstitute preferred modes for its practice. However, those of skill inthe art should, in light of the present disclosure, appreciate that manychanges can be made in the specific embodiments which are disclosed andstill obtain a like or similar result without departing from the spiritand scope of the invention.

EXAMPLE 1

[0044] Study #1 pERK/ERK

[0045] C6-ceramide has been shown in vitro and in vivo to prevent theup-regulation of extracellular signal-regulated kinase (ERK) to itsphosphorylated state (PERK) following balloon stretch injury. The lackof up-regulation in this kinase has been correlated to the prevention ofrestenosis in the rabbit carotid stretch injury model. Using thestandard rabbit carotid stretch injury model the activity ofoil-based/non-volatile formulations were screened. FIG. 1 shows theresults of this screening. As can be seen with the 1 % vitamin E (codename Kahlua) formulation, the effect on pERK following stretch injurywas not significantly different from the sham control artery that didnot receive any injury.

[0046] Study #2 Stenosis

[0047] In a parallel study a formulation containing 1% vitamin E, 0.5%propylene glycol, 0.05% Myrj 52 and 0.5% (w/w) C6-ceramide dissolved inethanol was evaluated in the rabbit carotid balloon injury model. Thesame procedure was used as above except the endpoint of this study was14 day histology to measure neointimal hyperplasia (NIH) as representedby the percentage decrease in the neointimal area of the injured artery(percent stenosis). Here, the oil-based formulation resulted in morethan a 50% reduction of neointimal hyperplasia (index of stenosis).

[0048] In both experiments it was possible to achieve equal or betterperformance from the oil-based formulation approaches compared to theexisting DMSO/C6-ceramide solvent-treated.

[0049] While the present invention has been described in some detail forpurposes of clarity and understanding, one skilled in the art willappreciate that various changes in form and detail can be made withoutdeparting from the true scope of the invention. All figures, tables, andappendices, as well as patents, applications, and publications, referredto above, are hereby incorporated by reference.

What is claimed is:
 1. A formulation for coating a medical device with ahydrophobic therapeutic agent, comprising the hydrophobic therapeuticagent, a non-volatile oil-based solvent, and an amount of a volatilesolvent sufficient to decrease the viscosity of the non-volatileoil-based solvent, such that the formulation is adapted to uniformlycoat the medical device.
 2. The formulation of claim 1, wherein thehydrophobic therapeutic agent is a restenosis-inhibiting agent.
 3. Theformulation of claim 2, wherein the hydrophobic restenosis-inhibitingagent is C6-ceramide.
 4. The formulation of claim 1, wherein thehydrophobic therapeutic agent is an anti-inflammatory agent.
 5. Theformulation of claim 1, wherein the hydrophobic therapeutic agent is ananti-oxidant.
 6. The formulation of claim 1, wherein the non-volatileoil-based solvent comprises Vitamin E.
 7. The formulation of claim 1,wherein the volatile solvent comprises an alcohol.
 8. The formulation ofclaim 7, wherein said alcohol comprises ethanol or isopropanol.
 9. Apharmaceutical formulation, comprising C6-ceramide and Vitamin E.
 10. Amedical device comprising a surface adapted to contact a vessel wall,wherein said surface has a coating comprising a hydrophobic therapeuticagent, and a non-volatile oil-based solvent in which said agent isdissolved.
 11. The medical device of claim 10, wherein said device is anintravascular balloon.
 12. The medical device of claim 10, wherein saiddevice is an intravascular stent.
 13. The medical device of claim 10,wherein said oil-based solvent comprises Vitamin E.
 14. The medicaldevice of claim 10, wherein said hydrophobic therapeutic agent is arestenosis-inhibiting agent.
 15. The medical device of claim 14, whereinsaid restenosis-inhibiting agent is C6-ceramide.
 16. A method forproducing a drug-coated intravascular device, comprising: producing acoating composition by mixing a drug composition comprising a drug andan oil-based non-volatile solvent in a volatile solvent, coating saidintravascular device with said coating composition; and causing saidvolatile solvent to evaporate.
 17. The method of claim 16, wherein saidoil-based non-volatile solvent comprises Vitamin E
 18. The method ofclaim 16, wherein said volatile solvent comprises an alcohol.
 19. Themethod of claim 18, wherein said alcohol is ethanol or isopropanol. 20.The method of claim 16, wherein said drug is hydrophobic.
 21. The methodof claim 20, wherein said hydrophobic drug is a restenosis-inhibitingagent.
 22. The drug-coated intravascular device produced by the methodof claim 16.